The oral route is the most preferable route of active ingredient administration because of several benefits, such as better patient compliance, safety and versatility. Therefore, a vast number of active ingredients is formulated in oral pharmaceutical dosage forms and mostly as solid pharmaceutical preparations, e.g. tablets, chewable tablets, capsules.
Nevertheless, there are some obstacles and difficulties when developing solid forms for oral administration, as many active pharmaceutical ingredients exhibit a low solubility in aqueous fluids which leads to decreased dissolution rate and limited therapeutic effect.
The aqueous solubility of an active ingredient is one of the most important physicochemical properties as low aqueous solubility and low dissolution rate can reduce the active ingredient absorption in the gastro-intestinal tract. Low active ingredient solubility also directs to decreased bioavailability, increased chance of food effect, more frequent incomplete release from the dosage form and higher interpatient variability.
Poorly water soluble active ingredients, namely compounds having solubility in water below 0.1 mg/ml, consist a large majority of the pharmaceutical active ingredients, thereby limiting their potential uses and increasing the difficulty of formulating bioavailable pharmaceutical products. In this category, disclosed are active ingredients such as Atorvastatin, Leflunomide, Raloxifene and Tadalafil.
Poorly soluble active ingredients have stimulated the development of active ingredient delivery technologies to overcome the obstacles to their solubilization through either chemical or mechanical modification of the environment surrounding the active ingredient molecule, or physically altering the macromolecular characteristics of aggregated active ingredient particles. These technologies include both traditional methods of solubility enhancement, such as particle size reduction, addition of surfactants and inclusion in cyclodextrin-active ingredient complexes, and the use of more novel mechanisms such as self-emulsifying systems, micronisation via nanoparticles, pH adjustment and salting-in processes.
Various methods are already known for the industrial preparation of dosage forms for oral administration comprising active pharmaceutical ingredients having low solubility. However, the prior art has encountered substantial difficulties in the production of oral solid formulations of a desirable bioavailability because of the very poor solubility of said active ingredient.
US-A-2006/068010 relates to a method for improving bioavailability of a low solubility active ingredient comprising orally administering a tablet or capsule comprising granules of said active ingredient with at least one amino acid and at least one intra-granular hydrophilic polymer, an immediate release excipient or a sustained release excipient.
WO-A-2005/041929 claims a solid oral dosage form comprising an active ingredient, a solubilizer and a release modulator, wherein the release of the active ingredient and solubilizer are synchronized.
Although each of the patents above represents an attempt to provide solid dosage forms for oral administration comprising poorly water soluble active ingredients, which overcome the related problems of low aqueous solubility and bioavailability of said active ingredient, there still exists the need for a simple, easy to operate and low-cost innovative process for formulating such active ingredients.